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Links found between brain enzyme, stress, neurological disorders

By Ross Tomlin

Shari Birnbaum, PhD

An enzyme identified by researchers at Baylor College of Medicine and Yale University could be linked to stress and other brain activities or functions. A report of their work appeared in a recent issue of the journal Science.

The collaborative study found that protein kinase C (PKC), an enzyme located inside brain cells, may play a critical role in neuropsychiatric disorders, such as schizophrenia, Tourette syndrome, movement disorders and dementia.

The study showed that activation of protein kinase C impairs proper memory function in the brain's prefrontal cortex, the most evolved brain system responsible for attention span, perseverance, planning, judgment, impulse control, organization, self-monitoring and supervision, problem solving, critical and forward thinking, learning from experience and mistakes, ability to feel and express emotions, empathy and internal supervision. When protein kinase C is activated, the result is dramatically decreased performance of ordinary tasks.

Scientists now believe that hyperactivity of this enzyme contributes not only to sensations of stress but also to behavioral conditions such as schizophrenia, bipolar disorder and attention deficit hyperactivity disorder.

Researchers observed a reduction in memory-related cell activity among rat and monkey models under exposure to conditions of stress and increased levels of this particular enzyme. In this instance, the conditions were induced by chemicals. Heightened levels of norepinephrine, a neurotransmitter (a molecule that transmits signals from one nerve cell to another across the synapse), coupled with PKC, were detected under these circumstances. Symptoms ranged from distractibility and poor judgment to thought disorder and possible hallucination.

"This study marks the first time PKC has been examined in the role of working memory and prefrontal function," said Shari Birnbaum, PhD, a BCM post-doctorate fellow in neuroscience and primary author of the journal article. "Our hypothesis was that during stress, there is an increase of norepinephrine, which activates PKC, and that this is how the memory impairments are occurring. Our goal was to find out if that was true and then to see whether we could block those effects."

Scientists have examined PKC before but only its role in long-term memory, which affects a different part of the brain (the hippocampus) than do short-term memory functions, said Birnbaum.

"The prefrontal cortex regulates daily activities and is used to call up long-term memories and guide your behavior," Birnbaum said. "It allows you to respond appropriately to input on thoughts in an appropriate manner. It is sort of the executive function of the brain."

Findings from the study may also provide a deeper understanding of the effects of lead poisoning, which causes symptoms resembling those of attention deficit hyperactivity disorder. Even very low concentrations of lead can activate PKC and weaken the ability of the prefrontal cortex to regulate behavior, causing poor impulse control and distractibility.

In the study, researchers suppressed PKC by giving the animals lithium and valproate, which resulted in improved working memory. Both chemicals are commonly prescribed to patients with bipolar disorder, yet their precise effect on the brain had been unclear.

"The goal is that once we understand how traditional drugs regulate behavior, we would then design new drugs that are more specific to certain pathways in the brain so that they will be more efficacious with fewer side effects," Birnbaum said.

Birnbaum and her researchers believe PKC inhibitors to be more quickly responsive and effective than traditional drugs such as lithium and carbamazepine. Birnbaum hopes some form of the inhibitors will eventually undergo clinical testing, at which point she expects pharmaceutical companies to make modifications that result in longer-lasting remedies.

"We do hope that eventually, whether it's the compound used in this study or some other compound that deactivates PKC, a drug would be able to be used effectively in patients, hopefully with few side effects," Birnbaum said. "Plus, when researchers look into these disorders in the future, they will do so both through genetics studies - to find a link to PKC - as well as through medicinal studies."

The PKC study was first set in motion at Yale University, where Birnbaum performed her graduate studies before entering a BCM post-doctorate program in neuroscience. In addition to the primary biochemistry work conducted at Baylor, behavioral analysis of the study took place at Yale, where Amy Arnsten, PhD, director of graduate studies, served as the study's principal investigator. Husseini Manji, MD, director of the NIMH's Mood and Anxiety Disorders Program, also performed biochemical experiments.

The study was funded by the National Institutes of Health's National Institute of Mental Health and National Institute of Aging, as well as the Stanley Foundation.

Science. 2004 Oct 29;306(5697):882-4.

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